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Novel immunotherapies in MM
dose was found to be 0.14 mg/kg every 3 weeks and, within the cohort given this dose (41 patients), the ORR was 61% (24% with a very good partial response and 37% with a partial response). This efficacy was similar to that observed in the belantamab mafodotin DREAMM-1 trial (Table 1).19
However, unexpected ocular toxicity occurred: 54% of the patients given the maximum tolerated dose devel- oped an as-yet unexplained photophobia. This toxicity, which led to treatment discontinuation in a large sub- group of patients, appears to be unrelated to the belan- tamab mafodotin-induced keratopathy. Other MEDI2228-induced toxicities were thrombocytopenia (32%), rash (29%) and pleural effusions (20%).18
AMG 224
The ADC AMG 224 is a BCMA-directed IgG1 mono- clonal antibody coupled to the tubulin inhibitor mertan- sine (also called DM1). The results of the first phase I dose expansion and escalation study (NCT02561962) have recently been reported.20 In all 40 patients, the ORR was 23%, including two patients with a stringent com- plete response and two with a very good partial response. The ADC was tolerated up to the defined maximum tol- erated dose of 190 mg intravenously every 3 weeks. Hematologic toxicity, mainly thrombocytopenia (40% ≥ grade 3), was the most common adverse event. No dose reductions, delays or ADC discontinuation were neces- sary due to ophthalmological adverse events (any grade: 30%). Ocular toxicity seems to be less common with this
ADC than with the MMAF-conjugated belantamab mafodotin (Table 1).20
The following ADC are in (pre-)clinical development, but no relevant clinical efficacy data have been reported so far.
CC99712
The ADC CC99712, which is currently being evaluated in a phase I study (NCT04036461), also targets BCMA. Its toxic payload is the tubulin inhibitor monomethyl auris- tatin E.9
TAK-169 and TAK-573
TAK-169 and TAK-573 are two CD38-directed ADC in early clinical development. TAK-169 is linked to a deim- munized Shiga-like toxin A subunit. Preclinical studies demonstrated highly effective lysis of primary MM cells in vitro.21 No clinical data regarding the ongoing phase I study (NCT04017130) are yet available. TAK-573 targets a CD38 epitope for which cross-reactivity with the cur- rently approved anti-CD38 monoclonal antibodies, dara- tumumab and isatuximab, is not anticipated. It is linked to two attenuated interferon α2b molecules. A first-in- human, dose-escalation, phase I trial (NCT 3215030), which is also assessing different treatment schedules, is currently recruiting patients. Early data focused on phar- macokinetic and immunological parameters have revealed limited clinical responses in MM patients across all four treatment cohorts.22
Table 1. Clinical trial results with antibody-drug conjugates.
ADC name Target Toxin Trial regimen Trial name Patients Prior lines
registration n. n (dose) of Tx (n)
Belantamab BCMA Monomethyl Monotherapy DREAMM-1 35 ≥5(57%)
ORR ≥ VGPR (%) (%)
PFS Toxicity Ref. (months) (selected)
mafodotin
auristatin F (MMAF)
Dose escalation and expansion
Monotherapy 2 doses: 2.5 mg/kg vs. 3.4mg/kg
2.5 mg/kg vs. 3.4 mg/kg
+ pembrolizumab
(NCT02064387)
DREAMM-2 (NCT03525678)
DREAMM-4 (NCT03848845)
(3.4 mg/kg)
97 (2.5 mg/kg)
60 54 12
31 22 2.8 35 27 3.9
67 50 NR
43 0
78 50 NR
88 68 NR 23 10 NR
61 24 NR
Keratopathy: 19 any grade: 69%
Thrombocytopenia any grade: 63%
Keratopathy 11 any grade: 70%
≥ grade 3: 27%
Keratopathy any grade: 75% ≥ grade 3: 21%
Keratopathy 13 any grade: 83%
any grade: 57%
Keratopathy 14 any grade: 100%
grade 3-4: 56%
Keratopathy 15 any grade: 76%
≥ grade 3: 51%
Thrombocytopenia 20 ≥ grade 3: 40%
Ocular toxicity:
any grade: 30%
Photophobia: 54% 18
99 6 (3.4 mg/kg)
7
AMG 224
MEDI2228
BCMA Mertansine (DM1)
BCMA Tesirine
(NCT02561962)
(NCT03489525)
40 (total)
41 (at MTD 0,14 mg/kg) (total: 82)
dexamethasone
+ pomalidomide / dexamethasone
Monotherapy Dose escalation and expansion
Monotherapy Dose escalation and expansion
Algonquin 37 (NCT03715478) (allcohorts)
DREAMM-6
18
6
(2.5 mg/kg)
7
(3.4 mg/kg)
7
5 3
3 7
2-11
2.5 vs. 3.4 mg/kg ArmB:+bortezomib/(NCT03544281) (2.5mg/kg)
Tx: treatment; ORR: overall response rate;VGPR: very good partial response; Ref: reference number; BCMA: B-cell maturation antigen; NR: not reported; MTD: maximal tolerated dose.
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